1. Technical Field of the Invention
The present invention relates to the administration of particular dithiolane compounds of formula (I) in compositions that are useful in the field of treating or preventing disorders of the skin induced by oxidative stress, especially caused by solar radiation, and to compositions containing them.
2. Description of Background and/or Related and/or Prior Art
The skin is the outermost organ of the body and is thus the first target for environmental stress factors, most particularly represented by the ultraviolet radiation of sunlight, UV-B and UV-A. Specifically, acute or chronic exposure to sunlight is known to induce deleterious biological and clinical effects on the body.
Skin damage caused by chronic exposure (repeated irradiation) or acute exposure (strong irradiation) to UV-A or UV-B has been extensively studied; it is especially known that:
UV-B rays (290-300 nm; 5% of the total UV), which have the most energetic wavelengths, most especially affect the epidermal cells (keratinocytes), by acting on DNA;
UV-A rays (320-400 nm; 95% of the total UV), which penetrate more deeply, reach the dermal cells such as the fibroblasts and act indirectly via the generation of free radicals;
furthermore, prolonged exposure to ultraviolet radiation has the effect of stimulating the expression of collagenases, particularly type 1 matrix metalloprotease (MMP-1).
At the cellular and molecular levels, the impact of UV-B and UV-A radiation induces various reactions, including direct and indirect induction of DNA lesions.
Among the direct induction of DNA lesions, some are specific to UV radiation, for instance pyrimidine dimers and 6,4 photo-produced. In the event of an error during repair by the specialized enzymatic systems (nucleotide excision repair NER, or global excision repair GER), they may be responsible for mutations that are themselves the cause of tumoral processes resulting in the development of skin cancers. Moreover, in cells derived from these tumors, a very high incidence of mutations characteristic of solar UV impact is found. These DNA lesions are also the cause of apoptosis processes inducing the formation of characteristic cells in the epidermis, the “sunburn cells”. It will also be noted that UV is responsible at the cellular level for the generation of reactive oxygen species, which are themselves the cause of many biological effects, such as the induction of oxidative DNA damage (8-oxoguanine) or the induction of numerous genes.
Finally, in addition to the effects mainly described on the two major cell types of the skin, namely the keratinocytes that form the stratified and differentiated epidermis, and the fibroblasts that are responsible for the synthesis and renewal of the dermal extracellular matrix, UV rays also have an impact on the Langerhans cells, which have an antigen-presenting immunity function.
The deleterious effects of UV rays on the skin (erythema, photocarcinogenesis, photoaging, photo-immunosuppression, etc.) are induced by the direct action of UV rays on certain cellular chromophores such as DNA, but also by indirect action. Specifically, the energy transported by UV rays is capable of triggering the formation of activated oxygen species (AOS), for instance singlet oxygen and the superoxide anion, by means of a photosensitization reaction involving endogenous photosensitizers such as riboflavins, bilirubins, phaeomelanin and porphyrin derivatives. The singlet oxygen and the superoxide anion undergo a cascade of reactions resulting in the production of other AOSs such as hydrogen peroxide and hydroxyl radicals. The AOSs thus generated damage DNA, cell membranes and certain proteins (enzymes, transcription factors, etc.).
Cells are equipped with an enzymatic antioxidant defense (Cu—Zn and Mn superoxide dismutases, catalases, glutathione peroxidases, etc.) and non-enzymatic antioxidant defense (vitamins E and C, thiols including glutathione, β-carotene, trace elements, etc.), whose role is to maintain the intracellular redox potential, but this defense capacity may be overloaded during an episode of intense oxidative stress.
The tripeptide glutathione (γ-L-glutamyl-L-cysteinylglycine or GSH) is the most widely occurring and abundant of the low molecular weight non-protein thiols. The majority of the intracellular GSH is found in reduced form (GSH). Glutathione disulfide (GSSG) is less than 0.5% of the total GSH. In most animal cells, the concentration of GSH is from 1 and 10 mM, whereas it is from about 0.5 and 10 μM in the plasma. The thiol function located on the cysteine residue gives it a redox potential (about −230 mV) that is predominant in redox metabolic phenomena. Its reductive and nucleophilic properties play a major role in protection against the oxidative impairment of fats, proteins and nucleic acids. Under a situation of oxidative stress, its protective and detoxifying role results mainly from its function as a coenzyme of glutathione peroxidases and glutathione-S-transferases. It also undergoes synergistic interactions with other components of the antioxidant protection system such as vitamin C, vitamin E, and superoxide dismutases.
Reducing the level of glutathione will thus affect the redox cellular balance. It is especially known that exposure to UV rays results in depletion of the level of intracellular GSH, thus increasing the sensitivity of the cells towards the oxidative stress.
Skin can be protected against the harmful effects of UV radiation by application of sunscreens. These products contain molecules that absorb the harmful wavelengths before they reach the skin and damage it, thus preventing the acute and chronic effects of exposure to UV rays.
However, sunscreens do not have a global action. Although no screening agent exists that allows total absorption of the harmful wavelengths (UV-B, UV-A and long UV-A), a photoprotection strategy based on induction of the endogenous antioxidant defense systems offers advantageous perspectives.
Thus, a real need exists to find or develop additional solutions in this field to reconstitute and/or preserve the level of endogenous glutathione after exposure to UV rays. This may be envisaged by stimulation with an active agent of the natural endogenous systems of cellular defense and/or repair after an episode of UV-induced stress.
Lipoic or thioctic acid (1,2-dithiacyclopentane-3-valeric acid) is an endogenous dithiol widely found in plants and animals. It is a coenzyme of fat and carbohydrate metabolism in mitochondrial multienzyme complexes such as pyruvate dehydrogenase and α-ketoglutarate dehydrogenase. Lipoic acid also increases the cellular level of glutathione by regenerating oxidized glutathione (GSSG) and increasing the activity of γ-glutamylcysteine ligase (an enzyme that controls the synthesis of GSH).
WO 2008/058 999 discloses siloxane or silane dithiolane compounds for increasing the level of glutathione after UV-induced depletion, especially the compound 5-(1,2-dithiolan-3-yl)-N-[3-(trimethylsilyl)propyl]pentanamide and the compound (trimethylsilyl)methyl 5-(1,2-dithiolan-3-yl)pentanoate. However, the protection afforded by these active agents against the UV-A daylight-induced depletion of GSH is still not fully satisfactory.